Abstract
Antibody-drug conjugates (ADCs) appear to be in a developmental boom, with five FDA approvals in the last two years and a projected market value of over $4 billion by 2024. Major advancements in the engineering of these novel cytotoxic drug carriers have provided a few early success stories. Although the use of these immunoconjugate agents are still in their infancy, valuable lessons in the engineering of these agents have been learned from both preclinical and clinical failures. It is essential to appreciate how the various mechanisms used to engineer changes in ADCs can alter the complex pharmacology of these agents and allow the ADCs to navigate the modern-day therapeutic challenges within oncology. This review provides a global overview of ADC characteristics which can be engineered to alter the interaction with the immune system, pharmacokinetic and pharmacodynamic profiles, and therapeutic index of ADCs. In addition, this review will highlight some of the engineering approaches being explored in the creation of the next generation of ADCs.
Highlights
This is reflected in the significant number of Antibody-drug conjugates (ADCs) compounds that fail to reach late-stage registration trials and even more that do not translate beyond preclinical studies [1]
PBDs are another type of anti-tumor antibiotic that work by forming dimers which in turn allows the compound to crosslink to opposing DNA strands [17]
While similar studies have not been performed in ADCs, it stands to reason that changes in the net ADC charge will influence an ADC’s rate of non-specific endocytosis, making charge modification an important physiochemical parameter
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Similar to the application of nano-technology to improve anti-cancer efficacy and reduce toxicity, this goal has been difficult to achieve with ADCs due to a seemingly narrow therapeutic index of the agents [3,4]. This is reflected in the significant number of ADC compounds that fail to reach late-stage registration trials and even more that do not translate beyond preclinical studies [1].
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